Isoxazole compositions useful as inhibitors of ERK

ABSTRACT

Described herein are compounds that are useful as protein kinase inhibitors, especially inhibitors of ERK, having the formula: 
                         
where A, B, R 1 , R 2 , T and Ht are described in the specification. The compounds are useful for treating diseases in mammals that are alleviated by a protein, kinase inhibitor, particularly diseases such as cancer, inflammatory disorders, restenosis, and cardiovascular disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.09/953,120, filed Sep. 14, 2001, now U.S. Pat. No. 6,495,582 whichclaims priority to U.S. Provisional Patent Application 60/232,956 filedSep. 15, 2000, the contents of which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention is in the field of medicinal chemistry and relatesto isoxazole compounds that are protein kinase inhibitors, especiallyinhibitors of ERK, compositions containing such compounds and methods ofuse. The compounds are useful for treating cancer and other diseasesthat are alleviated by protein kinase inhibitors.

BACKGROUND OF THE INVENTION

Mammalian mitogen-activated protein (MAP)1 kinases are serine/threoninekinases that mediate intracellular signal transduction pathways (Cobband Goldsmith, 1995, J. Biol. Chem. 270, 14843; Davis, 1995, Mol.Reprod. Dev. 42, 459). Members of the MAP kinase family share sequencesimilarity and conserved structural domains, and include the ERK(extracellular signal regulated kinase), JNK (Jun N-terminal kinase) andp38 kinases. JNKs and p38 kinases are activated in response to thepro-inflammatory cytokines TNF-alpha and interleukin-1, and by cellularstress such as heat shock, hyperosmolarity, ultraviolet radiation,lipopolysaccharides and inhibitors of protein synthesis (Derijard etal., 1994, Cell 76, 1025; Han et al., 1994, Science 265, 808; Raingeaudet al., 1995, J. Biol. Chem. 270, 7420; Shapiro and Dinarello, 1995,Proc. Natl. Acad. Sci. USA 92, 12230). In contrast, ERKs are activatedby mitogens and growth factors (Bokemeyer et al. 1996, Kidney Int. 49,1187).

ERK2 is a widely distributed protein kinase that achieves maximumactivity when both Thr183 and Tyr185 are phosphorylated by the upstreamMAP kinase kinase, MEK1 (Anderson et al., 1990, Nature 343, 651; Crewset al., 1992, Science 258, 478). Upon activation, ERK2 phosphorylatesmany regulatory-proteins, including the protein kinases Rsk90 (Bjorbaeket al., 1995, J. Biol. Chem. 270, 18848) and MAPKAP2 (Rouse et al.,1994, Cell 78, 1027), and transcription factors such as ATF2 (Raingeaudet al., 1996, Mol. Cell Biol. 16, 1247), Elk-1 (Raingeaud et al. 1996),c-Fos (Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952), andc-Myc (Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162). ERK2is also a downstream target of the Ras/Raf dependent pathways (Moodie etal., 1993, Science 260, 1658) and may help relay the signals from thesepotentially oncogenic proteins. ERK2 has been shown to play a role inthe negative growth control of breast cancer cells (Frey and Mulder,1997, Cancer Res. 57, 628) and hyperexpression of ERK2 in human breastcancer has been reported (Sivaraman et al., 1997, J. Clin. Invest. 99,1478). Activated ERK2 has also been implicated in the proliferation ofendothelin-stimulated airway smooth muscle cells, suggesting a role forthis kinase in asthma (Whelchel et al., 1997, Am. J. Respir. Cell Mol.Biol. 16, 589).

AKT, also known as protein kinase B, is a serine/threonine kinase thatplays a central role in promoting the survival of a wide range of celltypes [Khwaja, A., Nature, pp. 33-34 (1990)]. It has been shown by Zang,et al, that human ovarian cancer cells display elevated levels of AKT-1and AKT-2. Inhibition of AKT induces apoptosis of these human ovariancancer cells which demonstrates that AKT may be an important target forovarian cancer treatment [Zang, Q. Y., et al, Oncogene, 19 (2000)] andother proliferative disorders. The AKT pathway has also been implicatedin motoneuronal survival and nerve regeneration [Kazuhiko, N., et al,The Journal of Neuroscience, 20 (2000)].

U.S. Pat. No. 5,470,862 discloses an isoxazole compound as anintermediate in the preparation of intravenous anesthetics.

There is a high unmet medical need to develop protein kinase inhibitors,especially ERK and AKT inhibitors especially considering the currentlyavailable, relatively inadequate treatment options for the majority ofthese conditions.

Accordingly, there is still a great need to develop potent inhibitors ofprotein kinase, including ERK and AKT inhibitors, that are useful intreating various conditions associated with protein kinase activation.

DESCRIPTION OF THE INVENTION

It has now been found that compounds of this invention andpharmaceutical compositions thereof are effective as protein kinaseinhibitors, especially as inhibitors of ERK and AKT. These compoundshave the general formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

-   Ht is a heteroaryl ring selected from pyrrol-3-yl, pyrazol-3-yl,    [1,2,4]triazol-3-yl, [1,2,3]triazol-4-yl, or tetrazol-5-yl; said    pyrrol-3-yl and pyrazol-3-yl each having R³ and QR⁴ substituents,    and said triazole substituted by either R³ or QR⁴;-   A-B is N—O or O—N;-   R¹ is selected from R⁵, fluorine, N(R⁵)₂, OR, NRCOR, CON(R⁵)₂, SO₂R,    NRSO₂R, or SO₂N(R⁵)₂;-   T and Q are each independently selected from a valence bond or a    linker group;-   each R is independently selected from hydrogen or an optionally    substituted aliphatic group having one to six carbons;-   R² is selected from hydrogen, CN, fluorine, or an optionally    substituted group selected from aryl, heteroaryl, heterocyclyl, an    acyclic aliphatic group having one to six carbons, or acyclic    aliphatic group having four to ten carbons; wherein R² has up to one    L-W substituent and up to three R⁸ substituents;-   L is a C₁₋₆ alkylidene chain which is optionally substituted, and    wherein up to two methylene units of L are optionally replaced by    —C(O)—, —C(O)C(O)—, —CONH—, —CONHNH—, —CO₂—, —OC(O)—, —NHCO₂—, —O—,    —NHCONH—, —OC(O)NH—, —NHNH—, —NHCO—, —S—, —SO—, —SO₂—, —NH—,    —SO₂NH—, —NHSO₂NH—, or —NHSO₂—;-   W is selected from R⁹, CH(R⁹)₂, CH(R⁹)N(R⁹)₂, or N(R⁹)₂;-   R³ is selected from R, OH, OR, N(R)₂, fluorine, or CN;-   R⁴ is selected from —R⁶, —NH₂, —NHR⁶, —N(R⁶)₂, or —NR⁶    (CH₂)_(y)N(R⁶)₂;-   each R⁵ is independently selected from hydrogen or an optionally    substituted aliphatic group having one to six carbons or two R⁵ on    the same nitrogen may be taken together with the nitrogen to form a    four to eight membered ring having one to three heteroatoms;-   each R⁶ is independently selected from R⁵, —(CH₂)_(y)CH(R⁷)₂, or    —(CH₂)_(y)R⁷;-   y is 0-6;-   each R⁷ is an optionally substituted group independently selected    from R, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl,    heteroarylalkoxy, heterocyclyl, heterocyclylalkyl,    heterocyclylalkoxy, hydroxyalkyl, alkoxyalkyl; aryloxyalkyl, or    alkoxycarbonyl;-   each R⁸ is independently selected from halogen, —R′, —OR′, —SR′,    —NO₂, —CN, —N(R⁵)₂, —NRC(O)R′, —NRC(O)N(R⁵)₂, —NRCO₂R′, —NRNRC(O)R′,    —NRNRC(O)N(R⁵)₂, —NRNRCO₂R′, —C(O)C(O)R′, —C(O)CH₂C(O)R′, —CO₂R′,    —C(O)R′, —C(O)N(R⁵)₂, —OC(O)N(R⁵)₂, —S(O)₂R′, —SO₂N(R⁵)₂, —S(O)R′,    —NRSO₂N(R⁵)₂, —NRSO₂R′, —C(═S)N(R⁵)₂, or —C(═NH)N(R⁵)₂; wherein each    R′ is independently selected from hydrogen, or an optionally    substituted group selected from aliphatic, heteroaryl, heterocyclyl,    or phenyl; and-   each R⁹ is independently selected from R⁵, R⁸, or an optionally    substituted group selected from aryl, aralkyl, aralkoxy, heteroaryl,    heteroaralkyl, heterocyclyl, or heterocyclylalkyl.

As used herein, the following definitions shall apply unless otherwiseindicated. In addition, unless otherwise indicated, functional groupradicals are independently selected.

The term “aliphatic” as used herein means straight-chain, branched orcyclic C₁-C₁₂ hydrocarbons which are completely saturated or whichcontain one or more units of unsaturation but which are not aromatic.For example, suitable aliphatic groups include substituted orunsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”,“alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a largermoiety includes both straight and branched chains containing one totwelve carbon atoms. The terms “alkenyl” and “alkynyl” used alone or aspart of a larger moiety shall include both straight and branched chainscontaining two to twelve carbon atoms. The term “cycloalkyl” used aloneor as part of a larger moiety shall include cyclic C₃-C₁₂ hydrocarbonswhich are completely saturated or which contain one or more units ofunsaturation, but which are not aromatic.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “heteroatom” means N, O, or S and includes any oxidized form ofnitrogen and sulfur, and the quaternized form of any basic nitrogen. Italso includes ═N— and —NR⁺—, wherein R⁺ is as defined infra.

The term “carbocycle”, “carbocyclyl”, or “carbocyclic” as used hereinmeans an aliphatic ring system having three to fourteen members. Theterm “carbocycle”, “carbocyclyl”, or “carbocyclic” whether saturated orpartially unsaturated, also refers to rings that are optionallysubstituted. The terms “carbocyclyl” or “carbocyclic” also includealiphatic rings that are fused to one or more aromatic or nonaromaticrings, such as in a decahydronaphthyl or tetrahydronaphthyl, where theradical or point of attachment is on the aliphatic ring.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to aromatic ring groupshaving five to fourteen members, such as phenyl, benzyl, phenethyl,1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. The term “aryl”also refers to rings that are optionally substituted. The term “aryl”may be used interchangeably with the term “aryl ring”. “Aryl” alsoincludes fused polycyclic aromatic ring systems in which an aromaticring is fused to one or more rings. Examples include 1-naphthyl,2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scopeof the term “aryl”, as it is used herein, is a group in which anaromatic ring is fused to one or more non-aromatic rings, such as in aindanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical orpoint of attachment is on the aromatic ring.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinincludes non-aromatic ring systems having five to fourteen members,preferably five to ten, in which one or more ring carbons, preferablyone to four, are each replaced by a heteroatom such as N, O, or S.Examples of heterocyclic rings include 3-1H-benzimidazol-2-one,(1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl,3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, andbenzothianyl. Also included within the scope of the term “heterocyclyl”or “heterocyclic”, as it is used herein, is a group in which anon-aromatic heteroatom-containing ring is fused to one or more aromaticor non-aromatic rings, such as in an indolinyl, chromanyl,phenanthridinyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the non-aromatic heteroatom-containing ring. The term“heterocycle”, “heterocyclyl”, or “heterocyclic” whether saturated orpartially unsaturated, also refers to rings that are optionallysubstituted.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromatic ringgroups having five to fourteen members. Examples of heteroaryl ringsinclude 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl,5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl,3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl,indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl,benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, orbenzoisoxazolyl. Also included within the scope of the term“heteroaryl”, as it is used herein, is a group in which a heteroatomicring is fused to one or more aromatic or nonaromatic rings where theradical or point of attachment is on the heteroaromatic ring. Examplesinclude tetrahydroquinoline, tetrahydroisoquinoline, andpyrido[3,4-d]pyrimidinyl. The term “heteroaryl” also refers to ringsthat are optionally substituted. The term “heteroaryl” may be usedinterchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents. Examples of suitablesubstituents on the unsaturated carbon atom of an aryl, heteroaryl,aralkyl, or heteroaralkyl group include a halogen, —R^(o), —OR^(o),—SR^(o), 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such asacyloxy), phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph), —CH₂(Ph), substituted —CH₂ (Ph), —CH₂CH₂ (Ph), substituted —CH₂CH₂(Ph),—NO₂, —CN, —N(R^(o))₂, —NR^(o)C(O)R^(o), —NR^(o)C(O)N(R^(o))₂,—NR^(o)CO₂R^(o), —NR^(o) NR^(o)C(O)R^(o), —NR^(o) NR^(o)C(O)N(R^(o))₂,—NR^(o)NR^(o)CO₂R^(o), —C(O)C(O)R^(o), —C(O)CH₂C(O)R^(o), —CO₂R^(o),—C(O)R^(o), —C(O)N(R^(o))₂, —OC(O)N(R^(o))₂, —S(O)₂R^(o), —SO₂N(R^(o))₂,—S(O)R^(o), —NR^(o)SO₂N(R^(o))₂, —NR^(o)SO₂R^(o), —C(═S)N(R^(o))₂,—C(═NH)—N(R^(o))₂, —(CH₂)_(y)NHC(O)R^(o),—(CH₂)_(y)NHC(O)CH(V—R^(o))(R^(o)); wherein R^(o) is H, a substituted orunsubstituted aliphatic group, an unsubstituted heteroaryl orheterocyclic ring, phenyl (Ph), substituted Ph, —O(Ph), substituted—O(Ph), —CH₂(Ph), or substituted —CH₂(Ph); y is 0-6; and V is a linkergroup. Examples of substituents on the aliphatic group or the phenylring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen,alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl,alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

An aliphatic group or a non-aromatic heterocyclic ring may contain oneor more substituents. Examples of suitable substituents on the saturatedcarbon of an aliphatic group or of a non-aromatic heterocyclic ringinclude those listed above for the unsaturated carbon of an aryl orheteroaryl group and the following: ═O, ═S, ═NNHR*, ═NN(R*)₂,═N—,═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* isindependently selected from hydrogen, an unsubstituted aliphatic groupor a substituted aliphatic group. Examples of substituents on thealiphatic group include amino, alkylamino, dialkylamino, aminocarbonyl,halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano,carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, orhaloalkyl.

Suitable substituents on the nitrogen of an aromatic or non-aromaticheterocyclic ring include —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺,—C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, and—NR⁺SO₂R⁺; wherein R⁺ is H, an aliphatic group, a substituted aliphaticgroup, phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph), CH₂(Ph),substituted CH₂(Ph), or an unsubstituted heteroaryl or heterocyclicring. Examples of substituents on the aliphatic group or the phenyl ringinclude amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl,alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers are typically comprised of anatom such as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—,—C(O)NH—, or a chain of atoms, such as an alkylidene chain. Themolecular mass of a linker is typically in the range of about 14 to 200.Examples of linkers include a saturated or unsaturated C₁₋₆ alkylidenechain which is optionally substituted, and wherein one or two saturatedcarbons of the chain are optionally replaced by —C(O)—, —C(O)C(O)—,—CONH—, —CONH—, —CO₂—, —OC(O)—, —NHCO₂—, —O—, —NHCONH—, —OC(O)NH—,—NHNH—, —NHCO—, —S—, —SO—, —SO₂—, —NH—, —SO₂NH—, or —NHSO₂—.

The term “alkylidene chain” refers to an optionally substituted,straight or branched carbon chain that may be fully saturated or haveone or more units of unsaturation. The optional substituents are asdescribed above for an aliphatic group.

A combination of substituents or variables is permissible only if such acombination results in a stable or chemically feasible compound. Astable compound or chemically feasible compound is one that is notsubstantially altered when kept at a temperature of 40° C. or less, inthe absence of moisture or other chemically reactive conditions, for atleast a week.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

One embodiment of this invention relates to compounds wherein A—B isN—O, shown by formula II:

or a pharmaceutically acceptable derivative or prodrug thereof, whereinR¹, R², R³, R⁴, T, and Q are as described above. Preferred embodimentsof formula II are shown below for the Ht ring being pyrrol-3-yl (II-A),pyrazol-3-yl (II-B), [1,2,4]triazol-3-yl (II-C), [1,2,3]triazol-4-yl(II-D), and tetrazol-5-yl (II-E).

Preferred compounds of formulae II-A, II-B, II-C, II-D, and II-E includethose having one or more, and most preferably all, of the followingfeatures: (a) Q is —CO—, —CO₂—, or —CONH—; (b) T is a valence bond,—NHC(O)—, or —NHCH₂—; (c) R¹ is hydrogen or NHR; (d) R² is an optionallysubstituted aryl ring, preferably a phenyl ring, and more preferably aphenyl ring having up to one L-W substituent and up to three R⁸substituents; (e) W is selected from R⁹, CH(R⁹)₂, CH(R⁹)N(R⁹)₂, orN(R⁹)₂; (f) R³ is hydrogen; (g) R⁴ is selected from —R⁶, —NH₂, —NHR⁶,—N(R⁶)₂, or —NR⁶(CH₂)_(y)N(R⁶)₂; (h) R⁶ is R⁵, —(CH₂)_(y)CH(R⁷)₂, or—(CH₂)_(y)R⁷; and/or (i) R⁷ is an optionally substituted group selectedfrom aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, orheterocyclylalkyl.

Preferred R⁸ substituents on the R² phenyl group include halo, nitro,haloalkyl, hydroxyalkyl, C₁₋₆ aliphatic, alkoxy, amino, andheterocyclyl. Examples of preferred L groups include —CH₂—, CH₂NH—,—CH₂NHC(O)—, —NH—, —CH₂CH₂NH—, —CH₂O—; —CH₂C(O)NH—, —CH₂NHCH₂CH₂NHC(O)—,and —CH₂NHC(O)CH₂CH₂NHC(O)—. Preferred W groups include —CH(C₁₋₆aliphatic)NC(O)(C₁₋₆ aliphatic), —CH(CH₂OH)NC(O)(C₁₋₆ aliphatic),—CH(CH₂SH)NC(O)(C₁₋₆ aliphatic), —N(C₁₋₆ aliphatic)₂, -heterocyclyl(e.g. pyrrolidinyl, morpholinyl, thiomorpholinyl, and piperidinyl),—CH(C₁₋₆ aliphatic)NH₂, —CH(C₁₋₆ aliphatic)NC(O)O(C₁₋₆ aliphatic),—CH₂CN, and —CH₂N(C₁₋₆ aliphatic)₂.

When R⁴ is R⁶, preferred R⁶ groups include pyrrolidin-1-yl,morpholin-4-yl, piperidin-1-yl, and piperazin-1-yl wherein each group isoptionally substituted. When R⁴ is —NHR⁶ or —N(R⁶)₂, preferred R⁶ groupsfurther include (CH₂)_(y)R⁷ and —(CH₂)_(y)CH(R⁷)₂. Examples of preferredR⁶ and R⁷ include pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl,tetrahydrofuran-2-yl, cyclohexyl., phenyl, —CH₂OH, —(CH₂)₂OH, andisopropyl, wherein each group is optionally substituted.

Exemplary structures of formula II-A, wherein R¹ and R³ are eachhydrogen, are set forth in Table 1 below.

TABLE 1 Compounds. of Formula II-A II-A

No. T—R² Q—R⁴ IIA-1  phenyl CON(Me)₂ IIA-2  2-chlorophenyl CONHCH₂(Ph)IIA-3  2-chlorophenyl CO(morpholin-4-yl) IIA-4  4-methoxyphenylCONHCH₂(pyridin-4-yl) IIA-5  3-fluorophenyl CONHCH₂(pyridin-4-yl) IIA-6 3-methoxyphenyl CONHCH₂(pyridin-4-yl) IIA-7  2,5-dimethoxyphenylCONHCH₂(pyridin-4-yl) IIA-8  3,4-difluorophenyl CONHCH₂(pyridin-4-yl)IIA-9  2,3-difluorophenyl CONHCH₂(pyridin-4-yl) IIA-10 2,5-difluorophenyl CONHCH₂(pyridin-4-yl) IIA-11  4-methoxyphenylCONHCH₂(pyridin-3-yl) IIA-12  3-fluorophenyl CONHCH₂(pyridin-3-yl)IIA-13  3-methoxyphenyl CONHCH₂(pyridin-3-yl) IIA-14 2,5-dimethoxyphenyl CONHCH₂(pyridin-3-yl) IIA-15  3,4-difluorophenylCONHCH₂(pyridin-3-yl) IIA-16  2,3-difluorophenyl CONHCH₂(pyridin-3-yl)IIA-17  2,5-difluorophenyl CONHCH₂(pyridin-3-yl) IIA-18  4-methoxyphenylCONHCH₂(tetrahydrofuran-2-yl) IIA-19  3-fluorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-20  3-methoxyphenylCONHCH₂(tetrahydrofuran-2-yl) IIA-21  2,5-dimethoxyphenylCONHCH₂(tetrahydrofuran-2-yl) IIA-22  3,4-difluorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-23  2,3-difluorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-24  2,5-difluorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-25  4-fluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-26  4-methoxyphenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-27  3-fluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-28  3-methoxyphenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-29  2,5-dimethoxyphenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-30  3,4-difluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-31  2,3-difluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-32  2,5-difluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-33  4-fluorophenyl CO(morpholin-4-yl)IIA-34  4-methoxyphenyl CO(morpholin-4-yl) IIA-35  3-fluorophenylCO(morpholin-4-yl) IIA-36  3-methoxyphenyl CO(morpholin-4-yl) IIA-37 2,5-dimethoxyphenyl CO(morpholin-4-yl) IIA-38  2,3-difluorophenylCO(morpholin-4-yl) IIA-39  2,5-difluorophenyl CO(morpholin-4-yl) IIA-40 4-fluorophenyl CO(4-Me-piperazin-1-yl) IIA-41  4-methoxyphenylCO(4-Me-piperazin-1-yl) IIA-42  3-fluorophenyl CO(4-Me-piperazin-1-yl)IIA-43  3-methoxyphenyl CO(4-Me-piperazin-1-yl) IIA-44 2,5-dimethoxyphenyl CO(4-Me-piperazin-1-yl) IIA-45  2,3-difluorophenylCO(4-Me-piperazin-1-yl) IIA-46  2,5-difluorophenylCO(4-Me-piperazin-1-yl) IIA-47  3-chlorophenyl CONHCH₂(pyridin-4-yl)IIA-48  3-chlorophenyl CONHCH₂(pyridin-3-yl) IIA-49  3-chlorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-50  3-chlorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-51  3-chlorophenylCO(4-Me-piperazin-1-yl) IIA-52  4-chlorophenyl CONHCH₂(pyridin-4-yl)IIA-53  4-chlorophenyl CONHCH₂(pyridin-3-yl) IIA-54  4-chlorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-55  4-chlorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-56  4-chlorophenyl CO(morpholin-4-yl)IIA-57  4-chlorophenyl CO(4-Me-piperazin-1-yl) IIA-58 3,4-dichlorophenyl CONHCH₂(pyridin-3-yl) IIA-59  3,4-dichlorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-60  3,4-dichlorophenylCO(morpholin-4-yl) IIA-61  3,4-dichlorophenyl CO(4-Me-piperazin-1-yl)IIA-62  2-F-3-chlorophenyl CONHCH₂(pyridin-4-yl) IIA-63 2-F-3-chlorophenyl CONHCH₂(pyridin-3-yl) IIA-64  2-F-3-chlorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-65  2-F-3-chlorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-66  2-F-3-chlorophenylCO(morpholin-4-yl) IIA-67  2-F-3-chlorophenyl CO(4-Me-piperazin-1-yl)IIA-68  3-Cl-4-fluorophenyl CONHCH₂(pyridin-4-yl) IIA-69 3-Cl-4-fluorophenyl CONHCH₂(pyridin-3-yl) IIA-70  3-Cl-4-fluorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-71  3-Cl-4-fluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-72  3-Cl-4-fluorophenylCO(morpholin-4-yl) IIA-73  3-Cl-4-fluorophenyl CO(4-Me-piperazin-1-yl)IIA-74  3,4-dimethoxyphenyl CONHCH₂(pyridin-4-yl) IIA-75 3,4-dimethoxyphenyl CONHCH₂(pyridin-3-yl) IIA-76  3,4-dimethoxyphenylCONHCH₂(tetrahydrofuran-2-yl) IIA-77  3,4-dimethoxyphenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-78  3,4-dimethoxyphenylCO(morpholin-4-yl) IIA-79  3,4-dimethoxyphenyl CO(4-Me-piperazin-1-yl)IIA-80  4-benzo[1,3]dioxol-5-yl CONHCH₂(pyridin-4-yl) IIA-81 4-benzo[1,3]dioxol-5-yl CONHCH₂(pyridin-3-yl) IIA-82 4-benzo[1,3]dioxol-5-yl CONHCH₂(tetrahydrofuran-2-yl) IIA-83 4-benzo[1,3]dioxol-5-yl CONHCH₂(1-Et-pyrrolidin-2-yl) IIA-84 4-benzo[1,3]dioxol-5-yl CO(morpholin-4-yl) IIA-85 4-benzo[1,3]dioxol-5-yl CO(4-Me-piperazin-1-yl) IIA-86 3,5-dichlorophenyl CONHCH₂(pyridin-4-yl) IIA-87  3,5-dichlorophenylCONHCH₂(pyridin-3-yl) IIA-88  3,5-dichlorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-89  3,5-dichlorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-90  3,5-dichlorophenylCO(morpholin-4-yl) IIA-91  3,5-dichlorophenyl CO(4-Me-piperazin-1-yl)IIA-92  3-Cl-4-SO₂NH₂-phenyl CO(morpholin-4-yl) IIA-93  3-chlorophenylCO(morpholin-4-yl) IIA-94  phenyl pyridin-4-yl IIA-95  2-chlorophenylmorpholin-4-yl IIA-96  2-chlorophenyl CH₂(morpholin-4-yl) IIA-97 4-methoxyphenyl CH₂(pyridin-4-yl) IIA-98 

IIA-99 

IIA-100

IIA-101

IIA-102

IIA-103

IIA-104

IIA-105

IIA-106 phenyl

IIA-107 phenyl

IIA-108 3,4-dimethoxyphenyl

IIA-109 3-chlorophenyl

IIA-110 3-chlorophenyl

IIA-111 3-methylphenyl

IIA-112 3-chlorophenyl

IIA-113 2-fluoro-3-chlorophenyl

IIA-114 2-fluoro-3-chlorophenyl

IIA-115 3-chlorophenyl

IIA-116 3,4-dimethoxyphenyl

IIA-117 3,4-dimethoxyphenyl

IIA-118 3,4-dimethoxyphenyl

IIA-119 3-methylphenyl

IIA-120 2-fluoro-3-chlorophenyl

IIA-121 2-fluoro-3-chlorophenyl

IIA-122 2-fluoro-3-chlorophenyl

IIA-123 3-chlorophenyl

IIA-124 3,4-dimethoxyphenyl

IIA-125 2-fluoro-3-chlorophenyl

IIA-126 2-fluoro-3-chlorophenyl

IIA-127 3,4-dimethoxyphenyl

IIA-128 3,5-dichlorophenyl

IIA-129 3,5-dichlorophenyl

IIA-130 phenyl

IIA-131 phenyl

IIA-132 phenyl

IIA-133 phenyl

IIA-134 phenyl

IIA-135 3,4-dimethoxyphenyl

IIA-136 3,4-dimethoxyphenyl

IIA-137 3,4-dimethoxyphenyl

IIA-138 3-methylphenyl

IIA-139 3-methylphenyl

IIA-140 3-methylphenyl

IIA-141 2-fluoro,3-chlorophenyl

IIA-142 3-chlorophenyl

IIA-143 3-chlorophenyl

IIA-144 3-chlorophenyl

IIA-145 3-chlorophenyl

IIA-146 3-chlorophenyl

IIA-147 phenyl

IIA-148 phenyl

IIA-149 3,4-dimethoxyphenyl

IIA-150 3,4-dimethoxyphenyl

IIA-151 3-methylphenyl

IIA-152 3-methylphenyl

IIA-153 phenyl

IIA-154 phenyl

IIA-155 phenyl

IIA-156 3,4-dimethoxyphenyl

IIA-157 3,4-dimethoxyphenyl

IIA-158 3-methylphenyl

IIA-159 3-methylphenyl

IIA-160 3-chlorophenyl

IIA-161 phenyl

IIA-162 3-chlorophenyl

IIA-163 3,4-dimethoxyphenyl

IIA-164 3-chlorophenyl

IIA-165 phenyl

IIA-166 phenyl

IIA-167 phenyl

IIA-168 3,4-dimethoxyphenyl

IIA-169 3,4-dimethoxyphenyl

IIA-170 3,4-dimethoxyphenyl

IIA-171 3-methylphenyl

IIA-172 3-methylphenyl

IIA-173 3-methylphenyl

IIA-174 3-methylphenyl

IIA-175 3-methylphenyl

IIA-176 3-methylphenyl

IIA-177 2-fluoro,3-chlorophenyl

IIA-178 2-fluoro,3-chlorophenyl

IIA-179 2-fluoro,3-chlorophenyl

IIA-180 2-fluoro,3-chlorophenyl

IIA-181 phenyl

IIA-182 3-chlorophenyl

IIA-183 3-chlorophenyl

IIA-184 3-chlorophenyl

IIA-185 3-chlorophenyl

IIA-186 3-chlorophenyl

IIA-187 3-methylphenyl

IIA-188 3-methylphenyl

IIA-189 2-fluoro,3-chlorophenyl

IIA-190 2-fluoro,3-chlorophenyl

IIA-191 phenyl

IIA-192 3,4-dimethoxyphenyl

IIA-193 3-methylphenyl

IIA-194 phenyl

Another embodiment of this invention relates to compounds wherein A-B isO—N, shown by formula III:

or a pharmaceutically acceptable derivative or prodrug thereof, whereinR¹, R², T, and Q are as described above. Preferred embodiments offormula III are shown below for the Ht ring being pyrrol-3-yl (III-A),pyrazol-3-yl (III-B), [1,2,4]triazol-3-yl (III-C), [1,2,3]triazol-4-yl(III-D), and tetrazol-5-yl (III-E).

Preferred compounds of formulae III-A, III-B, III-C, III-D, and III-Einclude those having one or more, and most preferably all, of thefollowing features: (a) Q is —CO—, —CO₂—, or —CONH—; (b) T is a valencebond, —NHC(O)—, or —NHCH₂—; (c) R¹ is hydrogen or NHR; (d) R² is anoptionally substituted aryl ring, preferably a phenyl ring, and morepreferably a phenyl ring having up to one L-W substituent and up tothree R⁸ substituents; (e) W is selected from R⁹, CH(R⁹)₂, CH(R⁹)N(R⁹)₂,or N(R⁹)₂; (f) R³ is hydrogen; (g) R⁴ is selected from —R⁶, —NH₂, —NHR⁶,—N(R⁶)₂, or —NR⁶(CH₂)_(y)N(R⁶)₂; (h)R⁶ is R⁵, —(CH₂)_(y)CH(R⁷)₂, or—(CH₂)_(y)R⁷; and/or (i) R⁷ is an optionally substituted group selectedfrom aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, orheterocyclylalkyl.

Preferred R⁸ substituents of the R² phenyl group, if present, includehalo, nitro, haloalkyl, hydroxyalkyl, C₁₋₆ aliphatic, alkoxy, amino, andheterocyclyl. Preferred L groups include —CH₂—, —CH₂NH—, —CH₂NHC(O)—,—NH—, —CH₂CH₂NH—, —CH₂O—, —CH₂C(O)NH—, —CH₂NHCH₂CH₂NHC(O)—, and—CH₂NHC(O)CH₂CH₂NHC(O)—. Preferred W groups include —CH(C₁₋₆aliphatic)NC(O)(C₁₋₆ aliphatic), —CH(CH₂OH)NC(O)(C₁₋₆ aliphatic),—CH(CH₂SH)NC(O)(C₁₋₆ aliphatic), N(C₁₋₆ aliphatic)₂, heterocyclyl (e.g.pyrrolidinyl, morpholinyl, thiomorpholinyl, and piperidinyl), —CH(C₁₋₆aliphatic)NH₂, —CH(C₁₋₆ aliphatic)NC(O)O(C₁₋₆ aliphatic), —CH₂CN, and—CH₂N(C₁₋₆ aliphatic)₂.

When R⁴ is R⁶, preferred R⁶ groups include pyrrolidin-1-yl,morpholin-4-yl, piperidin-1-yl, and piperazin-1-yl wherein each group isoptionally substituted. When R⁴ is —NHR⁶ or —N(R⁶)₂, preferred R⁶ groupsfurther include (CH₂)_(y)R⁷ and —(CH₂)_(y)CH(R⁷)₂. Examples of preferredR⁶ and R⁷ include pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl,tetrahydrofuran-2-yl, cyclohexyl, phenyl, —CH₂OH, —(CH₂)₂OH, andisopropyl, wherein each group is optionally substituted.

Exemplary structures of formula III-A, wherein R¹ and R³ are eachhydrogen, are set forth in Table 2 below.

TABLE 2 Compounds of Formula III-A III-A

No. T—R² Q—R⁴ IIIA-1  phenyl CON(Me)₂ IIIA-2  2-chlorophenyl CONHCH₂(Ph)IIIA-3  2-chlorophenyl CO(morpholin-4-yl) IIIA-4  4-methoxyphenylCONHCH₂(pyridin-4-yl) IIIA-5  3-fluorophenyl CONHCH₂(pyridin-4-yl)IIIA-6  3-methoxyphenyl CONHCH₂(pyridin-4-yl) IIIA-7 2,5-dimethoxyphenyl CONHCH₂(pyridin-4-yl) IIIA-8  3,4-difluorophenylCONHCH₂(pyridin-4-yl) IIIA-9  2,3-difluorophenyl CONHCH₂(pyridin-4-yl)IIIA-10 2,5-difluorophenyl CONHCH₂(pyridin-4-yl) IIIA-11 4-methoxyphenylCONHCH₂(pyridin-3-yl) IIIA-12 3-fluorophenyl CONHCH₂(pyridin-3-yl)IIIA-13 3-methoxyphenyl CONHCH₂(pyridin-3-yl) IIIA-142,5-dimethoxyphenyl CONHCH₂(pyridin-3-yl) IIIA-15 3,4-difluorophenylCONHCH₂(pyridin-3-yl) IIIA-16 2,3-difluorophenyl CONHCH₂(pyridin-3-yl)IIIA-17 2,3-difluorophenyl CONHCH₂(pyridin-3-yl) IIIA-18 4-methoxyphenylCONHCH₂(tetrahydrofuran-2-yl) IIIA-19 2,5-difluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIIA-20 4-fluorophenyl CO(morpholin-4-yl)IIIA-21 4-fluorophenyl CO(4-Me-piperazin-1-yl)

According to another embodiment, the present invention relates tocompounds of formula IV:

or a pharmaceutically acceptable derivative or prodrug thereof, whereinR¹, R², T, and Q are as described above. Preferred embodiments offormula IV are shown below for the Ht ring being pyrrol-3-yl (IV-A),pyrazol-3-yl (IV-B), [1,2,4]triazol-3-yl (IV-C), [1,2,3]triazol-4-yl(IV-D), and tetrazol-5-yl (IV-E).

Preferred compounds of formulae IV-A, IV-B, IV-C, IV-D, and IV-E includethose having one or more, and most preferably all, of the followingfeatures: (a) Q is —CO—, —CO₂—, or —CONH—; (b) T is a valence bond,—NHC(O)—, or —NHCH₂—; (c) R² is an optionally substituted aryl ring,more preferably a phenyl ring having up to one L-W substituent and up tothree R⁸ substituents; (d) R³ is hydrogen; (e) R⁴ is selected from —R⁶,—NH₂, —NHR⁶, —N(R⁶)₂; or —NR⁶(CH₂)_(y)N(R⁶)₂; (f) R⁶ is R⁵,—(CH₂)_(y)CH(R⁷)₂, or —(CH₂)_(y)R⁷; and/or (g) R⁷ is an optionallysubstituted group selected from aryl, aralkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl group.

Preferred R⁸ substituents of the R² phenyl group, if present, includehalo, nitro, haloalkyl, hydroxyalkyl, C₁₋₆ aliphatic, alkoxy, amino, andheterocyclyl.

When R⁴ is R⁶, preferred R⁶ groups include pyrrolidin-1-yl,morpholin-4-yl, piperidin-1-yl, and piperazin-1-yl wherein each group isoptionally substituted. When R⁴ is —NHR⁶ or —N(R⁶)₂, preferred R⁶ groupsfurther include (CH₂)_(y)R⁷ and —(CH₂)_(y)CH(R⁷)₂. Examples of preferredR⁶ and R⁷ include pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl,tetrahydrofuran-2-yl, cyclohexyl, phenyl, —CH₂OH, —(CH₂)₂OH, andisopropyl, wherein each group is optionally substituted.

Exemplary structures of formula IV-A, wherein R³ is hydrogen, are setforth in Table 3 below.

TABLE 3 Compounds IV-A IV-A

No. R T—R² Q—R⁴ IVA-1  H phenyl CON(Me)₂ IVA-2  H phenyl CO₂Et IVA-3  H3-NO₂-phenyl CONHNH₂ IVA-4  H phenyl CO(pyrrolidin-1-yl) IVA-5  Mephenyl CONHCH₂(Ph) IVA-6  H 3-NO₂-phenyl CO₂Et IVA-7  H 4-Cl-phenylCO₂Et IVA-8  Me 4-OMe-phenyl CO₂Et IVA-9  H 3-NH₂-phenyl CO₂Et IVA-10 H3-OMe-phenyl CO₂Et IVA-11 H 4-F-phenyl CO₂Et IVA-12 H 4-NO₂-phenyl CO₂EtIVA-13 Et 3-Cl-phenyl CO₂Et IVA-14 H 3-F-phenyl CO₂Et IVA-15 H phenylCO₂H IVA-16 Me 3-Cl-phenyl CONHCH₂(pyridin-4-yl) IVA-17 H 5-Cl-phenyl

IVA-18 H 5-F-phenyl CONHCH₂(tetrahydrofuran-2-yl) IVA-19 Me5,6-F₂-phenyl CO(4-Me-piperidin-1-yl) IVA-20 H 4-Cl-phenylCONHCH₂(pyrid-4-yl) IVA-21 H 4,5-(OMe)₂-phenyl

IVA-22 Me 4,5-Cl₂-phenyl

IVA-23 H 3-Cl-phenyl

IVA-24 H 3-Cl-phenyl

IVA-25 Me 3,5-Cl₂-phenyl

IVA-26 H

IVA-27 H

CON(Me)₂

According to another embodiment, the present invention relates tocompounds, wherein T is a valence bond and R² is a phenyl ringsubstituted with L-W and up to three R⁸, of formula V:

or a pharmaceutically acceptable derivative or prodrug thereof, whereinR, R¹, R³, R⁴, R⁸, L, and W are as described above. Preferredembodiments are shown below for the Ht ring being pyrrol-3-yl (V-A),pyrazol-3-yl (V-B), [1,2,4]triazol-3-yl (V-C), [1,2,3]triazol-4-yl(V-D), and tetrazol-5-yl (V-E).

Preferred compounds of formulae V-A, V-B, V-C, V-D, and tetrazol-5-ylV-E include those having one or more, and most preferably all, of thefollowing features: (a) Q is —CO—, —CO₂—, or —CONH—; (b) R¹ is hydrogenor NHR; (c) W is selected from R⁹, CH(R⁹)₂, CH(R⁹)N(R⁹)₂, or N(R⁹)₂; (d)R³ is hydrogen; (e) R⁸, if present, is halogen, —R′, —OR′, —SR′, —NO₂,—CN, or —N(R⁵)₂; (f) R⁴ is selected from —R⁶, —NH₂, —NHR⁶, —N(R⁶)₂, or—NR⁶(CH₂)_(y)N(R⁶)₂; (g) R⁶ is R⁵, —(CH₂)_(y)CH(R⁷)₂, or —(CH₂)_(y)R⁷;and/or (h) R⁷ is an optionally substituted group selected from aryl,aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkylgroup.

Preferred R⁸ substituents of the R² phenyl group include halo, nitro,haloalkyl, hydroxyalkyl, C₁₋₆ aliphatic, alkoxy, amino, andheterocyclyl.

Preferred L groups include —CH₂—, —CH₂NH—, —CH₂NHC(O)—, —NH—,—CH₂CH₂NH—, —CH₂O—, —CH₂C(O)NH—, —CH₂NHCH₂CH₂NHC(O)—, and—CH₂NHC(O)CH₂CH₂NHC(O)—.

Preferred W groups include —CH(C₁₋₆ aliphatic)NC(O)(C₁₋₆ aliphatic),—CH(CH₂OH)NC(O)(C₁₋₆ aliphatic), —CH(CH₂SH)NC(O)(C₁₋₆ aliphatic), N(C₁₋₆aliphatic)₂, heterocyclyl (e.g. pyrrolidinyl, morpholinyl,thiomorpholinyl, and piperidinyl), —CH(C₁₋₆ aliphatic)NH₂, —CH(C₁₋₆aliphatic)NC(O)O(C₁₋₆ aliphatic), —CH₂CN, and —CH₂N(C₁₋₆ aliphatic)₂.

When R⁴ is R⁶, preferred R⁶ groups include pyrrolidin-1-yl,morpholin-4-yl, piperidin-1-yl, and piperazin-1-yl wherein each group isoptionally substituted. When R⁴ is —NHR⁶ or —N(R⁶)₂, preferred R⁶ groupsfurther include (CH₂)_(y)R⁷ and —(CH₂)_(y)CH(R⁷)₂. Examples of preferredR⁶ and R⁷ include pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl,tetrahydrofuran-2-yl, cyclohexyl, phenyl, —CH₂OH, —(CH₂)₂OH, andisopropyl, wherein each group is optionally substituted.

Exemplary structures of formula V-A, wherein R³ is hydrogen and T is avalence bond, are set forth in Table 4 below.

TABLE 4 Compounds of Formula V-A V-A

No. R¹ R² Q—R⁴ VA-1  H

CON(Me)₂ VA-2  H

CO₂Et VA-3  H

CONHNH₂ VA-4  NHMe

VA-5  NHMe

VA-6  NHMe

VA-7  NHEt

CONHCH₂(tetrahydrofuran-2-yl) VA-8  NHMe

CO(4-Me-piperidin-1-yl) VA-9  H

CONHCH₂(pyrid-4-yl) VA-10 H

VA-11 H

VA-12 H

VA-13 H

VA-14 H

VA-15 NH₂

CONHPh VA-16 NH₂

CONHCH₂(pyrid-4-yl) VA-17 NH₂

VA-18 NH₂

VA-19 H

VA-20 H

VA-21 H

VA-22 Me

VA-23 H

The present compounds may be prepared in general by methods known tothose skilled in the art for analogous compounds, as illustrated by thegeneral Schemes I, II, III, and IV below. These schemes are illustratedfor the pyrrole compounds of this invention and, by analogy, areapplicable for the preparation of compounds having the other Ht rings.

An array of compounds of formula II-A are prepared in the followingmanner, as shown in Scheme I above. In step (a), a series of separateFriedel-Crafts intermediates 2 are prepared from 2-trichloroacetylpyrrole (1) by treating a concentrated solution of the pyrrole and theappropriate acyl chloride with AlCl₃ in dichloroethane at 25° C. After 1hour, the resulting slurry is purified by chromatography to affordcompounds of formula 2.

In step (b), each compound 2 is first dissolved in DMF. A separatesolution of 1.2 equivalents of each of six amines 3 in DMF is alsoprepared. Using a Bohden parallel synthesizer, each compound 2 istreated with each amine 3. The reactions are performed at ambienttemperature for 24 hours then concentrated in vacuo to afford compoundsof formula 4.

In step (c), the concentrates of compound 4 are dissolved in THF. Usingthe Bohden parallel synthesizer, each compound 4 is then treated with asolution of (Me₂N)₂CHO-t-Bu in THF. The resulting mixtures are againstirred at ambient temperature for 48 hours then concentrated in vacuoto afford compounds of formula 5.

In step (d), the concentrates of compound 5 are first dissolved inethanol. Using the Bohden parallel synthesizer, each compound 5 istreated with K₂CO₃ and H₂NOH.HCl. The resulting mixtures are stirredunder reflux for 12 hours then concentrated in vacuo to afford compoundsof formula 6.

Each compound is purified by preparatory HPLC (Gilson) on a C18reverse-phase column eluted with a gradient of 10-90% MeCN (0.1% TFA) inwater over 15 minutes. The details of the conditions used to prepare thecompounds as described in Scheme I are set forth in the Examples.

As shown in Scheme II above using the preparation of compound IIIA-22 asan example, compounds of formula III-A may be prepared according to themethods of Zohdi, et al, J. Chem. Res., Synop (1991) 11, pp. 322-323.

Scheme III above depicts a general method for preparing compounds offormula I wherein T is NH₂, NH₂CH₂, or NH₂C(O) In step (a), thebromoacetyl compound 9 is treated with potassium phthalimide to form theprotected amino compound 10. Compound 10 is then treated withBrederick's reagent to form the enaminone compound 11. In step (c), theenaminone 11 is condensed with hydroxylamine to form the isoxazolecompouns which is treated with hydrazine in step (d) to remove thephthalimide protecting group to afford the amino compound 12. The aminocompound 12 may be derivatised with a variety of reagents to affordvarious compounds of formula I wherein T is other than a valence bond.For example, compound 12 is treated with a benzyl bromide derivative instep (e) to afford the benzylamine compound 13. In step (f), the aminocompound 12 is treated with a benzoyl chloride derivative to afford thebenzamide compound 14. Other compounds of formula I wherein T is otherthan a valence bond may be prepared by methods substantially similar tothose shown in Scheme III above by modifications of which are well knownto those skilled in the art.

Scheme IV above shows a general synthetic route that may be used forpreparing compounds of formula V-A. These compounds may be prepared bymethods substantially similar to those described in Scheme I above.

According to another embodiment, the invention provides a method ofinhibiting ERK or AKT kinase activity in a biological sample. Thismethod comprises the step of contacting said biological sample with acompound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

-   Ht is a heteroaryl ring selected from pyrrol-3-yl, pyrazol-3-yl,    [1,2,4]triazol-3-yl, [1,2,3]triazol-4-yl, or tetrazol-5-yl; said    pyrrol-3-yl and pyrazol-3-yl each having R³ and QR⁴ substituents,    and said triazole substituted by either R³ or QR⁴;-   A-B is N—O or O—N;-   R¹ is selected from R⁵, fluorine, N(R⁵)₂, OR, NRCOR, CON(R⁵)₂, SO₂R,    NRSO₂R, or SO₂N(R⁵)₂;-   T and Q are each independently selected from a valence bond or a    linker group;-   each R is independently selected from hydrogen or an optionally    substituted aliphatic group having one to six carbons;-   R² is selected from hydrogen, CN, fluorine, or an optionally    substituted group selected from aryl, heteroaryl, heterocyclyl, an    acyclic aliphatic group having one to six carbons, or a cyclic    aliphatic group having four to ten carbons; wherein R² has up to one    L-W substituent and up to three R⁸ substituents;-   L is a C₁₋₆ alkylidene chain which is optionally substituted, and    wherein up to two methylene units of L are optionally replaced by    —C(O)—, —C(O)C(O)—, —CONH—, —CONHNH—, —CO₂—, —OC(O)—, —NHCO₂—, —O—,    —NHCONH—, —OC(O)NH—, —NHNH—, —NHCO—, —S—, —SO—, —SO₂—, —NH—,    —SO₂NH—, —NHSO₂NH—, or —NHSO₂—;-   W is selected from R⁹, CH(R⁹)₂, CH(R⁹)N(R⁹)₂, or N(R⁹)₂;-   R³ is selected from R, OH, OR, N(R)₂, fluorine, or CN;-   R⁴ is selected from —R⁶, —NH₂, —NHR⁶, —N(R⁶)₂, or    —NR⁶(CH₂)_(y)N(R⁶)₂;-   each R⁵ is independently selected from hydrogen or an optionally    substituted aliphatic group having one to six carbons or two R⁵ on    the same nitrogen may be taken together with the nitrogen to form a    four to eight-membered ring having one to three heteroatoms;-   each R⁶ is independently selected from R⁵, —(CH₂)_(y)CH(R⁷)₂, or    —(CH₂)_(y)R⁷;-   y is 0-6;-   each R⁷ is an optionally substituted group independently selected    from R, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl,    heteroarylalkoxy, heterocyclyl, heterocyclylalkyl,    heterocyclylalkoxy, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or    alkoxycarbonyl;-   each R⁸ is independently selected from halogen, —R′, —OR′, —SR′,    —NO₂, —CN, —N(R⁵)₂, —NRC(O)R′, —NRC(O)N(R⁵)₂, —NRCO₂R′, —NRNRC(O)R′,    —NRNRC(O)N(R⁵)₂, —NRNRCO₂R′, —C(O)C(O)R′, —C(O)CH₂C(O)R′, —CO₂R′,    —C(O)R′, —C(O)N(R⁵)₂, —OC(O)N(R⁵)₂, —S(O)₂R′, —SO₂N(R⁵)₂, —S(O)R′,    —NRSO₂N(R⁵)₂, —NRSO₂R′, —C(═S)N(R⁵)₂, or —C(═NH)N(R⁵)₂; wherein each    R′ is independently selected from hydrogen, or an optionally    substituted group selected from aliphatic, heteroaryl, heterocyclyl,    or phenyl; and-   each R⁹ is independently selected from R⁵, R⁸, or an optionally    substituted group selected from aryl, aralkyl, aralkoxy, heteroaryl,    heteroaralkyl, heterocyclyl, or heterocyclylalkyl.

According to a preferred embodiment, the invention relates to a methodof inhibiting ERK or AKT kinase activity in a biological samplecomprising the step of contacting said biological sample with a compoundof formula formula II, III, IV, or V; more preferably with a compound offormula II-A, III-A, IV-A, or V-A; and most preferably, with a compoundlisted in Tables 1-4.

The term “biological sample”, as used herein includes cell cultures orextracts thereof; biopsied material obtained from a mammal or extractsthereof; and blood, saliva, urine, feces, semen, tears, or other bodyfluids or extracts thereof.

Another aspect of this invention relates to a method for treating adisease in a patient that is alleviated by treatment with an ERK or AKTprotein kinase inhibitor, which method comprises administering to apatient in need thereof a therapeutically effective amount of a compoundof formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

-   Ht is a heteroaryl ring selected from pyrrol-3-yl, pyrazol-3-yl,    [1,2,4]triazol-3-yl, [1,2,3]triazol-4-yl, or tetrazol-5-yl; said    pyrrol-3-yl and pyrazol-3-yl each having R³ and QR⁴ substituents,    and said triazole substituted by either R³ or QR⁴;-   A-B is N—O or O—N;-   R¹ is selected from R⁵, fluorine, N(R⁵)₂, OR, NRCOR, CON(R⁵)₂, SO₂R,    NRSO₂R, or SO₂N(R⁵)₂;-   T and Q are each independently selected from a valence bond or a    linker group;-   each R is independently selected from hydrogen or an optionally    substituted aliphatic group having one to six carbons;-   R² is selected from hydrogen, CN, fluorine, or an optionally    substituted group selected from aryl, heteroaryl, heterocyclyl, an    acyclic aliphatic group having one to six carbons, or a cyclic    aliphatic group having four to ten carbons; wherein R² has up to one    L-W substituent and up to three R⁸ substituents;-   L is a C₁₋₆ alkylidene chain which is optionally substituted, and    wherein up to two methylene units of L are optionally replaced by    —C(O)—, —C(O)C(O)—, —CONH—, —CONHNH—, —CO₂—, —OC(O)—, —NHCO₂—, —O—,    —NHCONH—, —OC(O)NH—, —NHNH—, —NHCO—, —S—, —SO—, —SO₂—, —NH—,    —SO₂NH—, —NHSO₂NH—, or —NHSO₂—;-   W is selected from R⁹, CH(R⁹)₂, CH(R⁹)N(R⁹)₂, or N(R⁹)₂;-   R³ is selected from R, OH, OR, N(R)₂, fluorine, or CN;-   R⁴ is selected from —R⁶, —NH₂, —NHR⁶, —N(R⁶)₂, or    —NR⁶(CH₂)_(y)N(R⁶)₂;-   each R⁵ is independently selected from hydrogen or an optionally    substituted aliphatic group having one to six carbons or two R⁵ on    the same nitrogen may be taken together with the nitrogen to form a    four to eight membered ring having one to three heteroatoms;-   each R⁶ is independently selected from R⁵, —(CH₂)_(y)CH(R⁷)₂, or    —(CH₂)_(y)R⁷;-   y is 0-6;-   each R⁷ is an optionally substituted group independently selected    from R, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl,    heteroarylalkoxy, heterocyclyl, heterocyclylalkyl,    heterocyclylalkoxy, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or    alkoxycarbonyl;-   each R⁸ is independently selected from halogen, —R′, —OR′, —SR′,    —NO₂, —CN, —N(R⁵)₂, —NRC(O)R′, —NRC(O)N(R⁵)₂, —NRCO₂R′, —NRNRC(O)R′,    —NRNRC(O)N(R⁵)₂, —NRNRCO₂R′, —C(O)C(O)R′, —C(O)CH₂C(O)R′, —CO₂R′,    —C(O)R′, —C(O)N(R⁵)₂, —OC(O)N(R⁵)₂, —S(O)₂R′, —SO₂N(R⁵)₂, —S(O)R′,    —NRSO₂N(R⁵)₂, —NRSO₂R′, —C(═S)N(R⁵)₂, or —C(═NH)N(R⁵)₂; wherein each    R′ is independently selected from hydrogen, or an optionally    substituted group selected from aliphatic, heteroaryl, heterocyclyl,    or phenyl; and-   each R⁹ is independently selected from R⁵, R⁸, or an optionally    substituted group selected from aryl, aralkyl, aralkoxy, heteroaryl,    heteroaralkyl, heterocyclyl, or heterocyclylalkyl.

A preferred embodiment comprises administering a compound of formula II,III, IV, or V, more preferably a compound of formula II-A, III-A, IV-A,or V-A, and most preferably, a compound listed in Tables 1-4.

Pharmaceutical compositions useful for such methods are described belowand are another aspect of the present invention.

The present method is especially useful for treating a disease that isalleviated by the use of an inhibitor of ERK.

The activity of the compounds as protein kinase inhibitors, for exampleas ERK inhibitors, may be assayed in vitro, in vivo or in a cell line.Using ERK as an example, in vitro assays include assays that determineinhibition of either the kinase activity or ATPase activity of activatedERK. Alternate in vitro assays quantitate the ability of the inhibitorto bind to ERK and may be measured either by radiolabelling theinhibitor prior to binding, isolating the inhibitor/ERK complex anddetermining the amount of radiolabel bound, or by running a competitionexperiment where new inhibitors are incubated with ERK bound to knownradioligands one may use any type or isoform of ERK, depending uponwhich ERK type or isoform is to be inhibited.

The protein kinase inhibitors of this invention, or pharmaceutical saltsthereof, may be formulated into pharmaceutical compositions foradministration to animals or humans. These pharmaceutical compositionseffective to treat or prevent a protein kinase-mediated condition whichcomprise the protein kinase inhibitor in an amount sufficient tomeasurably inhibit protein kinase activity (e.g., ERK or AKT activity)and a pharmaceutically acceptable carrier, are another embodiment of thepresent invention. The term “measurably inhibit”, as used herein means ameasurable change in activity between a sample containing said inhibitorand a sample containing only protein kinase.

The compounds of this invention are inhibitors of ERK and AKT kinase asdetermined by enzymatic assay. The details of the conditions used forthe enzymatic assays are set forth in the Examples hereinbelow.Accordingly, these compounds are useful for treating ERK- orAKT-mediated diseases or conditions.

The term “ERK-mediated disease” or “condition”, as used herein means anydisease or other deleterious condition in which ERK is known to play arole. Such conditions include, without limitation, cancer, stroke,diabetes, hepatomegaly, cardiovascular disease including cardiomegaly,Alzheimer's disease, cystic fibrosis, viral disease, autoimmunediseases, atherosclerosis, restenosis, psoriasis, allergic disordersincluding asthma, inflammation, neurological disorders andhormone-related diseases. The term “cancer” includes, but is not limitedto the following cancers: breast; ovary, cervix, prostate, testis,genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma,stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cellcarcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon,adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairycells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx,small intestine, colon-rectum, large intestine, rectum, brain andcentral nervous system, and leukemia.

The term “AKT-mediated disease” or “condition”, as used herein, meansany disease or other deleterious condition in which AKT is known to playa role. AKT-mediated diseases or conditions include, but are not limitedto, proliferative disorders, cancer, and neurodegenerative disorders.

In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified disorders.

A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a mammal (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

Pharmaceutically acceptable prodrugs of the compounds of this inventioninclude, without limitation, esters, amino acid esters, phosphateesters, metal salts and sulfonate esters.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acid salts includeacetate; adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate,pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,propionate, salicylate, succinate, sulfate, tartrate, thiocyanate,tosylate and undecanoate. Other acids, such as oxalic, while not inthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Salts derived from appropriate bases include alkali metal (e.g., sodiumand potassium), alkaline earth; metal (e.g., magnesium), ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions the quaternization ofany basic nitrogen-containing groups of the compounds disclosed herein.Water or oil-soluble or dispersible products may be obtained by suchquaternization.

Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or an oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of ERK or AKT inhibitor that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated, the particular mode of administration. Preferably, thecompositions should be formulated so that a dosage of between about0.01-100 mg/kg body weight/day of the inhibitor can be administered to apatient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of inhibitor will also depend upon the particular compound in thecomposition.

The kinase inhibitors of this invention or pharmaceutical compositionsthereof may also be incorporated into compositions for coating animplantable: medical device, such as prostheses, artificial valves,vascular grafts, stents and catheters. Vascular stents, for example,have been used to overcome restenosis (re-narrowing of the vessel wallafter injury). However, patients using stents or other implantabledevices risk clot formation or platelet activation. These unwantedeffects may be prevented or mitigated by pre-coating the device with acomposition comprising a kinase inhibitor. Suitable coatings and thegeneral preparation of coated implantable devices are described in U.S.Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.Implantable devices coated with a kinase inhibitor of this invention areanother embodiment of the present invention.

According to another embodiment, the invention provides methods fortreating or preventing an ERK- or AKT-mediated condition comprising thestep of administering to a patient one of the above-describedpharmaceutical compositions. The term “patient”, as used herein, meansan animal, preferably a mammal, and most preferably a human.

Preferably, that method is used to treat or prevent a condition selectedfrom cancers such as cancers of the breast, colon, prostate, skin,pancreas, brain, genitourinary tract, lymphatic system, stomach, larynxand lung, including lung adenocarcinoma and small cell lung cancer,stroke, diabetes, hepatomegaly, cardiomegaly, Alzheimer's disease,cystic fibrosis, and viral disease or any specific disease or disorderdescribed above.

Depending upon the particular ERK- or AKT-mediated condition to betreated or prevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may be administeredtogether with the ERK or AKT inhibitors of this invention. For example,chemotherapeutic agents or other anti-proliferative agents may becombined with the inhibitors of this invention to treat proliferativediseases and cancer. Examples of known chemotherapeutic agents include,but are not limited to, adriamycin, dexamethasone, vincristine,cyclophosphamide, fluorouracil, topotecan, taxol, interferons, andplatinum derivatives.

Other examples of therapeutic agents the inhibitors of this inventionmay also be combined with include, without limitation, anti-inflammatoryagents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; agents for treating diabetessuch as insulin, insulin analogues, alpha glucosidase inhibitors,biguanides, and insulin sensitizers; and agents for treatingimmunodeficiency disorders such as gamma globulin.

These additional therapeutic agents may be administered separately, aspart of a multiple dosage regimen, from the kinase inhibitor-containingcomposition. Alternatively, these agents may be part of a single dosageform, mixed together with the inhibitor in a single composition.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES Example 1

Compounds of formula II-A were prepared in the following manner inparallel fashion, as shown in Scheme I depicted above. In step (a), aseries of separate Friedel-Crafts intermediates 2 were prepared from2-trichloroacetyl pyrrole (1) by treating a concentrated solution of thepyrrole (1 equivalent) and the appropriate acyl chloride (1 equivalent)with AlCl₃ (1 equivalent) in minimal dichloroethane at 25° C. After 1hour, the resulting slurry was purified by silica gel chromatography toafford compounds of formula 2.

In step (b), each compound 2 was first dissolved in DMF. A separatesolution of 1.2 equivalents of each of six amines 3 in DMF was alsoprepared. Using a Bohden parallel synthesizer, each compound 2 wastreated with each amine 3. The reactions were performed at ambienttemperature for 24 hours then concentrated in vacuo to afford compoundsof formula 4.

In step (c), the concentrates of compound 4 were dissolved in THF. Usingthe Bohden parallel synthesizer, each compound 4 was then treated with asolution of (Me₂N)₂CH—O-t-Bu (10 equivalents) in THF. The resultingmixtures were again stirred at ambient temperature for 48 hours thenconcentrated in vacuo to afford compounds of formula 5.

In step (d), the concentrates of compound 5 were first dissolved inethanol. Using the Bohden parallel synthesizer, each compound 5 wastreated with, K₂CO₃ (2 equivalents) and H₂NOH.HCl (2.0 equivalents). Theresulting mixtures were stirred at reflux for 12 hours then concentratedin vacuo to afford compounds of formula 6.

Each compound was purified by preparatory HPLC (Gilson) on a C18reverse-phase column eluted with a gradient of 10-90% MeCN (0.1% TFA) inwater over 15 minutes. The characterization data for these compounds issummarized in Table 5 below and includes LC/MS, HPLC, and ¹H NMR data.

Unless otherwise indicated, the HPLC method used for the determinationof retention time is as follows: on a YMC ODS-AQ 55 120A column with asize of 3.0×150 mm, a gradient of water:MeCN, 0.1% TFA (95:5→0:100) wasrun over 15 minutes at 1 mL/min and 214 nm.

As used herein, the term “R_(t)” refers to the retention time, inminutes, obtained for the compound using the HPLC method as indicated.

Where applicable, ¹H NMR data is also summarized in Table 5 belowwherein “Y” designates ¹H NMR data is available and was found to beconsistant with structure. Compound numbers correspond to the compoundnumbers listed in Table 1.

TABLE 5 Characterization Data for Selected Compounds Compound No HPLCPurity IIA- M + 1 M − 1 (%) R_(t) (min) ¹H NMR  1 282 100 8.6 Y  3 358356 75 9.61 —  6 363 361 100 — — 15 381 379 93 — — 16 381 379 100 — — 17381 379 100 — — 23 374 372 100 — — 24 374 372 100 — — 29 425 423 98 — —30 401 399 100 — — 31 401 399 98 — — 32 401 399 100 — — 36 354 352 96 —— 37 384 — 90 — — 38 360 358 100 — — 39 360 358 75 — — 42 355 354 100 —— 43 365 363 100 — — 44 397 — 92 — — 45 373 371 100 — — 46 373 371 100 —— 47 354 352 85 7.92 Y 48 379 377 84 7.96 — 49 372 370 90 9.82 — 50 399397 87 8.37 — 51 371 369 83 7.56 — 52 379 377 100 8.02 — 53 379 377 1007.83 — 54 372 370 95 9.91 — 55 399 397 95 8.44 — 56 358 356 73 9.64 — 57371 369 83 7.66 — 58 413 411 93 8.6 — 59 433 431 100 9.09 — 60 392 39074 10.35 — 61 405 403 70 8.26 — 62 397 395 100 7.99 — 63 397 395 1007098 — 64 390 388 100 9.75 — 65 417 415 89 8.42 — 66 — — 86 9.54 — 67389 387 68 7.67 — 68 — — 89 8.1 — 69 — — 100 8.13 — 70 390 — 81 10.01 —71 417 415 100 8.56 — 72 376 374 96 9.75 — 73 389 387 62 7.78 — 74 405403 97 6.9 — 75 405 403 93 6.9 — 76 398 396 85 8.43 — 77 425 423 1007.27 — 78 384 382 83 8.1 — 79 397 395 98 6.59 — 80 389 387 100 7.29 — 81389 387 100 7.29 — 82 382 380 100 8.91 — 83 409 407 100 7.7 — 84 368 —88 8.65 — 85 381 379 80 6.97 — 86 413 411 100 8.69 — 87 413 411 100 8.67— 88 406 404 72 10.84 — 89 433 431 100 9.13 — 90 392 390 72 10.54 — 91405 403 74 8.26 — 92 — — 92 — Y 93 358 356 100 — Y

Example 2

ERK Inhibition Assay

Compounds were assayed for the inhibition of ERK2 by aspectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7,2249). In this assay, a fixed concentration of activated ERK2 (10 nM)was incubated with various concentrations of the compound in DMSO (2.5%)for 10 min. at. 30° C. in 0.1 M HEPES buffer, pH 7.5, containing 10 mMMgCl₂, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvatekinase, 50 μg/mL lactate dehydrogenase, and 200 μM erktide peptide. Thereaction was initiated by the addition of 65 μM ATP and the rate ofdecrease of absorbance at 340 nM was monitored. The percent inhibitionvalues were determined at an inhibitor concentration of 10 μM.

Table 6 shows the results of the activity of selected compounds of thisinvention in the ERK2 inhibition assay. The compound numbers correspondto the compound numbers in Table 1. Compounds having an activitydesignated as “A” provided a percent inhibition value above 60%;compounds having an activity designated as “B” provided a percentinhibition value between 30 and 60%; and compounds having an activitydesignated as “C” provided a percent inhibition value less than 30%.

TABLE 6 ERK2 Inhibitory Activity of Selected Compounds No. Activity No.Activity IIA-1 B IIA-3 B IIA-4 C IIA-5 B IIA-6 C IIA-7 C IIA-8 A IIA-9 AIIA-10 A IIA-11 B IIA-12 B IIA-13 B IIA-15 B IIA-16 B IIA-17 B IIA-18 CIIA-19 B IIA-20 B IIA-22 C IIA-23 B IIA-24 A IIA-25 C IIA-26 C IIA-27 CIIA-28 C IIA-29 C IIA-36 B IIA-37 C IIA-38 B IIA-39 B IIA-40 C IIA-41 CIIA-42 C IIA-43 C IIA-44 C IIA-45 C IIA-46 C IIA-47 A IIA-48 A IIA-49 BIIA-50 C IIA-51 C IIA-52 A IIA-53 B IIA-54 C IIA-55 C IIA-56 C IIA-57 CIIA-58 B IIA-59 C IIA-60 B IIA-61 C IIA-62 A IIA-63 A IIA-64 B IIA-65 CIIA-66 B IIA-67 C IIA-68 A IIA-69 B IIA-70 B IIA-71 C IIA-72 B IIA-73 CIIA-74 B IIA-80 B IIA-81 B IIA-82 B IIA-84 C IIA-86 A IIA-87 B IIA-88 BIIA-90 C IIA-91 C IIA-106 B IIA-107 B IIA-108 B IIA-109 B IIA-110 BIIA-111 B IIA-112 A IIA-113 B IIA-114 A IIA-115 B IIA-116 B IIA-117 CIIA-118 C IIA-119 B IIA-120 A IIA-121 B IIA-122 C IIA-123 C IIA-124 CIIA-125 C IIA-126 B IIA-127 B IIA-130 B IIA-131 C IIA-132 C IIA-133 BIIA-134 A IIA-135 C IIA-136 C IIA-137 C IIA-138 C IIA-139 C IIA-140 BIIA-141 C IIA-142 C IIA-143 A IIA-144 A IIA-145 B IIA-146 B IIA-147 BIIA-148 B IIA-149 C IIA-150 B IIA-151 B IIA-152 C IIA-153 C IIA-155 BIIA-156 C IIA-157 C IIA-158 B IIA-159 C IIA-160 B IIA-161 C IIA-162 CIIA-164 C IIA-165 C IIA-166 C IIA-167 B IIA-171 A IIA-172 B IIA-173 CIIA-174 C IIA-175 A IIA-176 C IIA-177 C IIA-178 C IIA-179 C IIA-180 CIIA-181 C IIA-182 B IIA-183 B IIA-184 C IIA-185 C IIA-186 C IIA-187 CIIA-188 C IIA-189 B IIA-190 C IIA-191 C — —

Example 3

AKT3 Inhibition Assay

Compounds were screened for their ability to inhibit AKT3 using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mMMgCl2, 25 mM NaCl, 1 mM DTT and 1.5% DMSO. Final substrateconcentrations in the assay were 170 μM ATP (Sigma Chemicals) and 200 μMpeptide (RPRAATF, American Peptide, Sunnyvale, Calif.). Assays werecarried out at 30° C. and 45 nM AKT3. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ML pyruvate kinase and 10 μg/ml lactatedehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of AKT3, DTT, and the testcompound of interest. 56 μl of the stock solution was placed in a 384well plate followed by addition of 1 μl of 2 mM DMSO stock containingthe test compound (final compound concentration 30 μM). The plate waspreincubated for about 10 minutes at 30° C. and the reaction initiatedby addition of 10 μl of enzyme (final concentration 45 nM) and 1 mM DTT.Rates of reaction were obtained using a BioRad Ultramark plate reader(Hercules, Calif.) over a 5 minute read time at 30° C.

Table 7 shows the results of the activity of selected compounds of thisinvention in the AKT3 inhibition assay. The compound numbers correspondto the compound numbers in Table 1. Compounds having an activitydesignated as “A” provided a percent inhibition value above 30%;compounds having an activity designated as “B” provided a percentinhibition value between 20 and 30%; and compounds having an activitydesignated as “C” provided a percent inhibition value less than 20%. Allpercent inhibition values were determined at a 30 μM inhibitorconcentration.

TABLE 7 AKT3 Inhibitory Activity of Selected Compounds No. Activity No.Activity IIA-106 B IIA-107 A IIA-108 B IIA-109 A IIA-110 B IIA-111 BIIA-112 B IIA-113 B IIA-114 A IIA-115 B IIA-116 A IIA-117 A IIA-118 AIIA-119 A IIA-120 A IIA-121 C IIA-122 A IIA-123 A IIA-124 C IIA-125 CIIA-126 B IIA-127 B IIA-131 C IIA-132 B IIA-133 C IIA-134 C IIA-135 CIIA-136 C IIA-139 C IIA-140 C IIA-141 C IIA-142 C IIA-143 A IIA-144 CIIA-145 C IIA-146 C IIA-147 C IIA-148 C IIA-150 C IIA-151 B IIA-153 AIIA-155 C IIA-156 C IIA-159 C IIA-160 C IIA-161 C IIA-162 C IIA-163 AIIA-164 A IIA-165 C IIA-166 C IIA-167 C IIA-171 C IIA-172 B IIA-173 BIIA-174 C IIA-175 C IIA-176 C IIA-177 C IIA-178 C IIA-179 C IIA-180 AIIA-181 C IIA-182 B IIA-183 C IIA-184 C IIA-185 C IIA-186 C IIA-187 CIIA-188 C IIA-189 B — —

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments which have been represented by way of example.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ht ispyrrol-3-yl having R³ and QR⁴ substituents; A-B is N—O or O—N; R¹ ishydrogen or —NHR; T is a valence bond; Q is —C(O) or —SO₂—; each R isindependently selected from hydrogen or an optionally substitutedaliphatic group having one to six carbons; R² is an aryl groupsubstituted with up to three R⁸ substituents; R³ is hydrogen; R⁴ is —R⁶or —NHR⁶; each R⁶ is independently selected from —(CH₂)_(y)R⁷; y is 0-6;each R⁷ is an optionally substituted group independently selected fromaryl, heteroaryl, or heterocyclyl; each R⁸ is independently selectedfrom halogen, —R′, or —OR′; wherein each R′ is independently selectedfrom hydrogen, or an optionally substituted C₁₋₁₂ aliphatic.
 2. Thecompound according to claim 1 having the formula:

or a pharmaceutically acceptable salt thereof.
 3. The compound accordingto claim 2 having the formula:

or a pharmaceutically acceptable salt thereof.
 4. The compound accordingto claim 3, wherein said compound has one or more features selected fromthe group consisting of: (a) Q is —CO—; (b) R¹ is hydrogen; (c) R⁷ is anoptionally substituted heterocyclyl group.
 5. The compound according toclaim 4, wherein: (a) Q is —CO—; (b) R¹ is hydrogen; and (c) R⁷ is anoptionally substituted heterocyclyl group.
 6. The compound according toclaim 1 having the formula:

or a pharmaceutically acceptable salt thereof.
 7. The compound accordingto claim 6 having the formula:

or a pharmaceutically acceptable salt thereof.
 8. The compound accordingto claim 7, wherein said compound has one or more features selected fromthe group consisting of: (a) Q is —CO—; (b) R¹ is hydrogen; (c) R⁷ is anoptionally substituted heterocyclyl group.
 9. The compound according toclaim 8, wherein: (a) Q is —CO—; (b) R¹ is hydrogen; (c) R⁷ is anoptionally substituted heterocyclyl group.
 10. The compound according toclaim 1 having the formula:

or a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 10 having the formula:

or a pharmaceutically acceptable salt thereof.
 12. The compoundaccording to claim 11, wherein said compound has one or more featuresselected from the group consisting of: (a) Q is —CO—; (b) R⁷ is anoptionally substituted heterocyclyl group.
 13. The compound according toclaim 12, wherein: (a) Q is —CO—; (b) R⁷ is an optionally substitutedheterocyclyl group.
 14. The compound according to claim 1, wherein saidcompound is selected from the following compounds having formulae II-Aor and IV-A: TABLE 1 Compounds of Formula II-A II-A

No. T—R² Q—R⁴ IIA-2  2-chlorophenyl CONHCH₂(Ph) IIA-3  2-chlorophenylCO(morpholin-4-yl) IIA-4  4-methoxyphenyl CONHCH₂(pyridin-4-yl) IIA-5 3-fluorophenyl CONHCH₂(pyridin-4-yl) IIA-6  3-methoxyphenylCONHCH₂(pyridin-4-yl) IIA-7  2,5-dimethoxyphenyl CONHCH₂(pyridin-4-yl)IIA-8  3,4-difluorophenyl CONHCH₂(pyridin-4-yl) IIA-9 2,3-difluorophenyl CONHCH₂(pyridin-4-yl) IIA-10  2,5-difluorophenylCONHCH₂(pyridin-4-yl) IIA-11  4-methoxyphenyl CONHCH₂(pyridin-3-yl)IIA-12  3-fluorophenyl CONHCH₂(pyridin-3-yl) IIA-13  3-methoxyphenylCONHCH₂(pyridin-3-yl) IIA-14  2,5-dimethoxyphenyl CONHCH₂(pyridin-3-yl)IIA-15  3,4-difluorophenyl CONHCH₂(pyridin-3-yl) IIA-16 2,3-difluorophenyl CONHCH₂(pyridin-3-yl) IIA-17  2,5-difluorophenylCONHCH₂(pyridin-3-yl) IIA-18  4-methoxyphenylCONHCH₂(tetrahydrofuran-2-yl) IIA-19  3-fluorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-20  3-methoxyphenylCONHCH₂(tetrahydrofuran-2-yl) IIA-21  2,5-dimethoxyphenylCONHCH₂(tetrahydrofuran-2-yl) IIA-22  3,4-difluorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-23  2,3-difluorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-24  2,5-difluorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-25  4-fluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-26  4-methoxyphenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-27  3-fluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-28  3-methoxyphenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-29  2,5-dimethoxyphenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-30  3,4-difluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-31  2,3-difluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-32  2,5-difluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-33  4-fluorophenyl CO(morpholin-4-yl)IIA-34  4-methoxyphenyl CO(morpholin-4-yl) IIA-35  3-fluorophenylCO(morpholin-4-yl) IIA-36  3-methoxyphenyl CO(moroholin-4-yl) IIA-37 2,5-dimethoxyphenyl CO(morpholin-4-yl) IIA-38  2,3-difluorophenylCO(morpholin-4-yl) IIA-39  2,5-difluorophenyl CO(morpholin-4-yl) IIA-40 4-fluorophenyl CO(4-Me-piperazin-1-yl) IIA-41  4-methoxyphenylCO(4-Me-piperazin-1-yl) IIA-42  3-fluorophenyl CO(4-Me-piperazin-1-yl)IIA-43  3-methoxyphenyl CO(4-Me-piperazin-1-yl) IIA-44 2,5-dimethoxyphenyl CO(4-Me-piperazin-1-yl) IIA-45  2,3-difluorophenylCO(4-Me-piperazin-1-yl) IIA-46  2,5-difluorophenylCO(4-Me-piperazin-1-yl) IIA-47  3-chlorophenyl CONHCH₂(pyridin-4-yl)IIA-48  3-chlorophenyl CONHCH₂(pyridin-3-yl) IIA-49  3-chlorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-50  3-chlorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-51  3-chlorophenylCO(4-Me-piperazin-1-yl) IIA-52  4-chlorophenyl CONHCH₂(pyridin-4-yl)IIA-53  4-chlorophenyl CONHCH₂(pyridin-3-yl) IIA-54  4-chlorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-55  4-chlorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-56  4-chlorophenyl CO(morpholin-4-yl)IIA-57  4-chlorophenyl CO(4-Me-piperazin-1-yl) IIA-58 3,4-dichlorophenyl CONHCH₂(pyridin-3-yl) IIA-59  3,4-dichlorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-60  3,4-dichlorophenylCO(morpholin-4-yl) IIA-61  3,4-dichlorophenyl CO(4-Me-piperazin-1-yl)IIA-62  2-F-3-chlorophenyl CONHCH₂(pyridin-4-yl) IIA-63 2-F-3-chlorophenyl CONHCH₂(pyridin-3-yl) IIA-64  2-F-3-chlorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-65  2-F-3-chlorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-66  2-F-3-chlorophenylCO(morpholin-4-yl) IIA-67  2-F-3-chlorophenyl CO(4-Me-piperazin-1-yl)IIA-68  3-Cl-4-fluorophenyl CONHCH₂(pyridin-4-yl) IIA-69 3-Cl-4-fluorophenyl CONHCH₂(pyridin-3-yl) IIA-70  3-Cl-4-fluorophenylCONHCH₂(tetrahydrofuran-2-yl) IIA-71  3-Cl-4-fluorophenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-72  3-Cl-4-fluorophenylCO(morpholin-4-yl) IIA-73  3-Cl-4-fluorophenyl CO(4-Me-piperazin-1-yl)IIA-74  3,4-dimethoxyphenyl CONHCH₂(pyridin-4-yl) IIA-75 3,4-dimethoxyphenyl CONHCH₂(pyridin-3-yl) IIA-76  3,4-dimethoxyphenylCONHCH₂(tetrahydrofuran-2-yl) IIA-77  3,4-dimethoxyphenylCONHCH₂(1-Et-pyrrolidin-2-yl) IIA-78  3,4-dimethoxyphenylCO(morpholin-4-yl) IIA-79  3,4-dimethoxyphenyl CO(4-Me-piperazin-1-yl)IIA-80  4-benzo[1,3]dioxol- CONHCH₂(pyridin-4-yl) 5-yl IIA-81 4-benzo[1,3]dioxol- CONHCH₂(pyridin-3-yl) 5-yl IIA-82 4-benzo[1,3]dioxol- CONHCH₂(tetrahydrofuran-2-yl) 5-yl IIA-83 4-benzo[1,3]dioxol- CONHCH₂(1-Et-pyrrolidin-2-yl) 5-yl IIA-84 4-benzo[1,3]dioxol- CO(morpholin-4-yl) 5-yl IIA-85  4-benzo[1,3]dioxol-CO(4-Me-piperazin-1-yl) 5-yl IIA-86  3,5-dichlorophenylCONHCH₂(pyridin-4-yl) IIA-87  3,5-dichlorophenyl CONHCH₂(pyridin-3-yl)IIA-88  3,5-dichlorophenyl CONHCH₂(tetrahydrofuran-2-yl) IIA-89 3,5-dichlorophenyl CONHCH₂(1-Et-pyrrolidin-2-yl) IIA-90 3,5-dichlorophenyl CO(morpholin-4-yl) IIA-91  3,5-dichlorophenylCO(4-Me-piperazin-1-yl) IIA-93  3-chlorophenyl CO(morpholin-4-yl)IIA-106 phenyl

IIA-107 phenyl

IIA-108 3,4-dimethoxyphenyl

IIA-109 3-chlorophenyl

IIA-110 3-chlorophenyl

IIA-111 3-methylphenyl

IIA-114 2-fluoro-3-chlorophenyl

IIA-115 3-chlorophenyl

IIA-116 3,4-dimethoxyphenyl

IIA-117 3,4-dimethoxyphenyl

IIA-119 3-methylphenyl

IIA-120 2-fluoro-3-chlorophenyl

IIA-121 2-fluoro-3-chlorophenyl

IIA-122 2-fluoro-3-chlorophenyl

IIA-123 3-chlorophenyl

IIA-124 3,4-dimethoxyphenyl

IIA-125 2-fluoro-3-chlorophenyl

IIA-126 2-fluoro-3-chlorophenyl

IIA-130 phenyl

IIA-131 phenyl

IIA-132 phenyl

IIA-133 phenyl

IIA-134 phenyl

IIA-135 3,4-dimethoxyphenyl

IIA-136 3,4-dimethoxyphenyl

IIA-137 3,4-dimethoxyphenyl

IIA-138 3-methylphenyl

IIA-139 3-methylphenyl

IIA-140 3-methylphenyl

IIA-141 2-fluoro,3-chlorophenyl

IIA-142 3-chlorophenyl

IIA-143 3-chlorophenyl

IIA-144 3-chlorophenyl

IIA-145 3-chlorophenyl

IIA-146 3-chlorophenyl

IIA-148 phenyl

IIA-150 3,4-dimethoxyphenyl

IIA-151 3-methylphenyl

IIA-152 3-methylphenyl

IIA-153 phenyl

IIA-154 phenyl

IIA-155 phenyl

IIA-156 3,4-dimethoxyphenyl

IIA-157 3,4-dimethoxyphenyl

IIA-159 3-methylphenyl

IIA-160 3-chlorophenyl

IIA-161 phenyl

IIA-162 3-chlorophenyl

IIA-163 3,4-dimethoxyphenyl

IIA-164 3-chlorophenyl

IIA-165 phenyl

IIA-167 phenyl

IIA-168 3,4-dimethoxyphenyl

IIA-169 3,4-dimethoxyphenyl

IIA-170 3,4-dimethoxyphenyl

IIA-171 3-methylphenyl

IIA-172 3-methylphenyl

IIA-173 3-methylphenyl

IIA-174 3-methylphenyl

IIA-175 3-methylphenyl

IIA-176 3-methylphenyl

IIA-177 2-fluoro-3-chlorophenyl

IIA-179 2-fluoro-3-chlorophenyl

IIA-180 2-fluoro-3-chlorophenyl

IIA-182 3-chlorophenyl

IIA-183 3-chlorophenyl

IIA-184 3-chlorophenyl

IIA-187 3-methylphenyl

IIA-190 2-fluoro,3-chlorophenyl

IIA-191 phenyl

IIA-192 3,4-dimethoxyphenyl

IIA-193 3-methylphenyl

IIA-194 phenyl

TABLE 2 Compounds of Formula IV-A IV-A

No. R T—R² Q—R⁴ IVA-4  H phenyl CO(pyrrolidin-1-yl) IVA-5  Me phenylCONHCH₂(Ph) IVA-16 Me 3-Cl-phenyl CONHCH₂(pyridin-4-yl) IVA-17 H5-Cl-phenyl

IVA-18 H 5-F-phenyl CONHCH₂(tetrahydrofuran-2-yl) IVA-19 Me5,6-F₂-phenyl CO(4-Me-piperidin-1-yl) IVA-20 H 4-Cl-phenylCONHCH₂(pyrid-4-yl) IVA-21 H 4,5-(OMe)₂-phenyl

IVA-22 Me 4,5-Cl₂-phenyl


15. A composition comprising a compound according to claim 1 and apharmaceutically acceptable carrier.
 16. The composition according toclaim 15 wherein said compound is formulated in a pharmaceuticallyacceptable manner for administration to a patient.
 17. The compositionaccording to claim 15 further comprising an additional therapeutic agentselected from a chemotherapeutic agent, an anti-inflammatory agent, animmunomodulatory or immunosuppressive agent, a neurotrophic factor, anagent for treating liver disease, an agent for treating a blooddisorder, an agent for treating diabetes, or an agent for treating animmunodeficiency disorder.
 18. The composition according to claim 16further comprising an additional therapeutic agent selected from achemotherapeutic agent, an anti-inflammatory agent, an immunomodulatoryor immunosuppressive agent, a neurotrophic factor, an agent for treatingliver disease, an agent for treating a blood disorder, an agent fortreating diabetes, or an agent for treating an immunodeficiencydisorder.
 19. A method of inhibiting ERK or AKT activity in a biologicalsample selected from cell cultures or extracts thereof, biopsiedmaterial obtained from a mammal or extracts thereof, saliva, urine,feces, semen, tears, or extracts thereof, comprising the step ofcontacting said biological sample in vitro with a compound according toclaim 1 or a composition according to claim 15.